Insulin resistance (IR), also known as metabolic syndrome, is tied to obesity and is associated with numerous modern health problems including the growing problems of type 2 diabetes and cardiovascular disease. The growing health, economic and social burdens of these conditions calls for the need to develop drug treatments for IR. We know from multiple lines of evidence that mtDNA serves as a molecular sentinel, controlling cell fate in response to oxidant stress. There is a conspicuous association between mtDNA damage and oxidant induced cell death (the propensity for cytotoxicity is inversely related to the efficiency of mtDNA repair). Also, a growing body of evidence suggests that integrity of mitochondrial DNA (mtDNA) is crucial in the IR progression. The mtDNA is highly specialized and encodes for proteins essential for energy metabolism and free radical production, very critical for insulin signaling. With respect to IR, we have found that the extent f mtDNA damage directly correlates to obesity-induced IR. Using a genetic approach, the targeting of Exscien's fusion protein construct Exscien1-I to mitochondria (containing the DNA repair enzyme human 8-oxoguanine DNA glycosylase, hOGG1) has shown to significantly improve insulin sensitivity in transgenic MTS-hOGG1 mice. Essentially, by overexpressing the repair enzyme at the point of oxidative stress we have attenuated the level of mtDNA damage and the IR side effects. We now propose to fully verify the level of efficacy of mitochondria-targeted DNA repair drugs in the obesity-induced mouse model of IR. The intent of this Phase I proposal is to establish proof-of-concept that pharmacologic enhancement of mtDNA repair attenuates the degree of IR. This proposed application is innovative because it will herald first-in-class, molecules directed against a novel target in metabolic syndrome, mtDNA.